Transcriptomic profiling of lymphocytic colitis highlights distinct diarrhoeal pathomechanisms

Background and Aims: The pathobiology of the non-destructive inflammatory bowel disease (IBD) lymphocytic colitis (LC) is poorly understood. Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways. Methods: We performed whole mucosa bulk RNA-sequencing of LC and CC samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn’s disease patients (n=4 per group) to distinguish non-destructive from classic IBD. Results: The LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation. Conclusions: We conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention. Whole colonic mucosa mRNA profiles of lymphocytic colitis (LC), collagenous colitis (CC), and healthy controls (Hc).